The formation, maintenance, and reorganization of synapses are critical for brain development and the responses of neuronal circuits to environmental challenges. Here we describe a novel role for peroxisome proliferator-activated receptor gamma co-activator (PGC-1α), a master regulator of mitochondrial biogenesis, in the formation and maintenance of dendritic spines in hippocampal neurons. In cultured hippocampal neurons, PGC-1α overexpression increases dendritic spines and enhances the molecular differentiation of synapses, whereas knockdown of PGC-1α inhibits spinogenesis and synaptogenesis.. PGC-1α knockdown also reduces the density of dendritic spines in hippocampal dentate granule neurons in vivo. We further show that brain-derived neurotrophic factor (BDNF) stimulates PGC-1α-dependent mitochondrial biogenesis by activating ERKs and CREB. PGC-1α knockdown inhibits BDNF to promote dendritic spine formation without affecting expression and activation of the BDNF receptor TrkB. Our findings suggest that PGC-1α and mitochondrial biogenesis play important roles in the formation and maintenance of hippocampal dendritic spines and synapses.
Recent extensive studies have revealed that molecular hydrogen (H 2 ) has great potential for improving oxidative stress-related diseases by inhaling H 2 gas, injecting saline with dissolved H 2 , or drinking water with dissolved H 2 (H 2 -water); however, little is known about the dynamic movement of H 2 in a body. First, we show that hepatic glycogen accumulates H 2 after oral administration of H 2 -water, explaining why consumption of even a small amount of H 2 over a short span time efficiently improves various disease models. This finding was supported by an in vitro experiment in which glycogen solution maintained H 2 . Next, we examined the benefit of ad libitum drinking H 2 -water to type 2 diabetes using db/db obesity model mice lacking the functional leptin receptor. Drinking H 2 -water reduced hepatic oxidative stress, and significantly alleviated fatty liver in db/db mice as well as high fat-diet-induced fatty liver in wild-type mice. Long-term drinking H 2 -water significantly controlled fat and body weights, despite no increase in consumption of diet and water. Moreover, drinking H 2 -water decreased levels of plasma glucose, insulin, and triglyceride, the effect of which on hyperglycemia was similar to diet restriction. To examine how drinking H 2 -water improves obesity and metabolic parameters at the molecular level, we examined gene-expression profiles, and found enhanced expression of a hepatic hormone, fibroblast growth factor 21 (FGF21), which functions to enhance fatty acid and glucose expenditure. Indeed, H 2 stimulated energy metabolism as measured by oxygen consumption. The present results suggest the potential benefit of H 2 in improving obesity, diabetes, and metabolic syndrome.
Molecular hydrogen (H(2)) is an efficient antioxidant that diffuses rapidly across cell membranes, reduces reactive oxygen species (ROS), such as hydroxyl radicals and peroxynitrite, and suppresses oxidative stress-induced injury in several organs. ROS have been implicated in radiation-induced damage to lungs. Because prompt elimination of irradiation-induced ROS should protect lung tissue from damaging effects of irradiation, we investigated the possibility that H(2) could serve as a radioprotector in the lung. Cells of the human lung epithelial cell line A549 received 10 Gy irradiation with or without H(2) treatment via H(2)-rich PBS or medium. We studied the possible radioprotective effects of H(2) by analyzing ROS and cell damage. Also, C57BL/6J female mice received 15 Gy irradiation to the thorax. Treatment groups inhaled 3% H(2) gas and drank H(2)-enriched water. We evaluated acute and late-irradiation lung damage after H(2) treatment. H(2) reduced the amount of irradiation-induced ROS in A549 cells, as shown by electron spin resonance and fluorescent indicator signals. H(2) also reduced cell damage, measured as levels of oxidative stress and apoptotic markers, and improved cell viability. Within 1 wk after whole thorax irradiation, immunohistochemistry and immunoblotting showed that H(2) treatment reduced oxidative stress and apoptosis, measures of acute damage, in the lungs of mice. At 5 mo after irradiation, chest computed tomography, Ashcroft scores, and type III collagen deposition demonstrated that H(2) treatment reduced lung fibrosis (late damage). This study thus demonstrated that H(2) treatment is valuable for protection against irradiation lung damage with no known toxicity.
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